The recently identified ningalin class of marine natural products including ningalin B (1) possess a common 3,4-diaryl substituted pyrrole nucleus bearing a 2-carboxylate. Ningalin B (1) is the second member of this newly described family of marine natural products which were isolated by Fenical (1997) from an ascidian of the genus Didemnum collected in western Australia near Ningaloo Reef. (Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254) Consequently, 1 and the related ningalins are the newest members of a family of 3,4-dihydroxyphenylalanine (DOPA)-derived o-catechol metabolites that include the tunichromes. (Bruening, R. C.; et al. J. Am. Chem. Soc. 1985, 107, 5289; Bruening, R. C.; et al. J. Nat. Prod. 1986, 49, 193; Bayer, E; et al. Angew. Chem. Int. Ed. Engl. 1992, 31, 52; Oltz, E. M.; et al. J. Am. Chem. Soc. 1988, 110, 6162; Ryan, D. E.; et al. J. Am. Chem. Soc. 1992, 114, 9659; Taylor, S. W.; et al. Arch. Biochem. Biophys. 1995, 324, 228)
The lamellarins are a related rapidly growing class of marine natural products which were first isolated from the prosobranch mollusc Lamellaria sp. and important members of this class have been disclosed by Bowden, Faulkner, Fenical, Capon, and Scheuer. (Lamellarins A-D: Anderson, R. J.; et al. J. Am. Chem. Soc. 1985, 107, 5492. Lamellarins E-H: Lindquist, N.; et al. J. Org. Chem. 1988, 53, 4570. Lamellarins I-N: Carroll, A. R.; et al. Aust. J. Chem. 1993, 46, 489. Lamellarins O, P: Urban, S.; et al. Aust. J. Chem. 1994, 47, 1919. Lamellarins Q, R: Urban, S.; et al. Aust. J. Chem. 1995, 48, 1491. Lamellarins S: Urban, S.; et al. Aust. J. Chem. 1996, 49, 711. Lamellarins T-X: Reddy, R. M.; et al. Tetrahedron 1997, 53, 3457. Lamellarin Z: Davis, R. H.; et al. J. Nat. Prod. 1999, 62, 419. Lukianol A, B: Yoshida, W. Y.; et al. Helv. Chim. Acta 1992, 75, 1721.) Recent investigations of several lamellarins demonstrated their cytotoxic activity, revealed equally effective cytotoxic activity against multidrug-resistant (MDR) cell lines, and revealed MDR reversal even at noncytotoxic concentrations by inhibition of P-glycoprotein (P-gp) mediated drug efflux. (Quesada, A. R.; et al. Br. J. Cancer 1996, 74, 677.) Thus, they constitute a new class of antitumor agents which reverse MDR more effectively than verapamil and resensitize resistant malignant cells to front line therapeutics. A number of related structures have been defined that lack cytotoxic activity but which effectively reverse MDR. (Ningalin A, lamellarin O, lukianol A, and permethyl storniamide A: Boger, D. L.; et al. J. Am. Chem. Soc. 1999, 121, 54.)
What is needed is a new class of MDR reversal agents having potent activity for resensitizing resistant cancer cells with respect to effective anticancer agents.